Merkel cell carcinoma (MCC) is a rare but highly aggressive form of skin cancer that features the expression of neuroendocrine markers. MCCs characteristically exhibit a high propensity for invasion and metastasis; however, the etiology and cellular origin of MCC remain unknown. Moreover, the incidence of MCC cases has tripled over the last decade with less than half of MCC patients surviving one year following detection of lymph node involvement. Human epidemiological data indicates that exposure to ultraviolet radiation is a major risk factor for MCC development. In addition, a novel human polyomavirus, Merkel cell polyomavirus (MCPyV), was identified in 80% of human cutaneous MCC suggesting that large T antigen transformation may play a causative role in the pathogenesis of MCC. Despite this progress, our severe lack of understanding of the biology of the target cells that give rise to MCC significantly hinders efforts to define the causal elements of this lesion. The studies outlined in this proposal are based on our recent discovery of a discrete population of epithelial keratinocytes in the epidermis of skin that serve as the progenitor cell reservoir responsible for sustaining the normal Merkel cell lineage. This progenitor cell population resides in touch domes in the hairy skin and is unique in its capacity to maintain normal Merkel cell turnover. Our preliminary studies suggest that these touch dome progenitors may also be a target cell for MCC. To assess this, we have generated a novel transgenic mouse model for MCC based on our preliminary findings and we will employ this model to test the hypothesis that i) touch dome progenitor cells are the cells of origin for normal and neoplastic Merkel cells and ii) that ultraviolet radiation in combination with large T antigen expression is sufficient for Merkel cell carcinogenesis. Our ability to pinpoint the critical pathological components of MCC will provide a significant leap forward in the development of effective therapeutic strategies for these fatal cancers. PUBLIC HEALTH RELEVANCE: Chronic exposure to sunlight is the underlying cause of 90% of skin cancers. This proposal is designed to better understand exactly how solar radiation influences the development of a highly aggressive form of skin cancer called Merkel cell carcinoma. In particular, we will assess the role of two significant risk factors for Merkel cell carcinoma in humans, ultraviolet radiation and viral oncogenes, on the formation Merkel cell carcinoma in a newly develop experimental mouse model.